The Importance of Acetyl Coenzyme A Synthetase for 11C-Acetate Uptake and Cell Survival in Hepatocellular Carcinoma

We analyzed the pattern of C-11-acetate and F-18-FDG uptake on PET/CT in patients with hepatocellular carcinoma (HCC). We also assessed the expression of important regulatory enzymes related to glycolysis and lipid synthesis in relation to F-18-FDG and C-11-acetate uptake in human HCC cell lines. The significance of C-11-acetate uptake regulation was further evaluated with regard to cell viability. Methods: F-18-FDG and C-11-acetate uptake patterns in HCC in 11 patients and in 5 HCC cell lines were assessed. We evaluated the gene expression of metabolic enzymes related to glycolysis and lipid synthesis in a cell line with the highest F-18-FDG uptake and another cell line with the highest C-11-acetate uptake. They included hexokinase II, adenosine triphosphate citrate lyase, acetyl coenzyme A (CoA) synthetase 1 (ACSS1), acetyl CoA synthetase 2 (ACSS2), acetyl CoA carboxylase, and fatty acid synthase. In a cell line with high C-11-acetate uptake, the enzymatic activities of ACSS1 and ACSS2 were blocked using respective small, interfering RNAs (siRNAs), and the impact on C-11-acetate uptake and cell viability was assessed. Results: In all 11 patients and 4 of the 5 cell lines, the uptake patterns of the 2 radiotracers were complementary. ACSS1 and ACSS2 were highly expressed in a cell line with low F-18-FDG uptake and high C-11-acetate uptake, whereas only ACSS2 was expressed in a cell line with high F-18-FDG uptake and low C-11-acetate uptake. Fatty acid synthase expression was seen in cells with high v or C-11-acetate uptake. These findings indicate the possibility that both glucose and acetate can be a compensatory carbon source for lipid synthesis in cancer. Transient transfection with ACSS1 or ACSS2 siRNA in cells with high C-11-acetate uptake decreased C-11-acetate uptake and cell viability. Conclusion: The patterns of F-18-FDG and C-11-acetate uptake seemed to complement each other in both human HCC and HCC cell lines. Fatty acid synthase expression was seen in cells with high F-18-FDG or C-11-acetate uptake, suggesting glucose-or acetate-dependent lipid synthesis. Acetyl CoA synthetase appears to be important in C-11-acetate uptake and acetate-dependent lipid synthesis for the growth of cancer cells with a low-glycolysis phenotype. Inhibition of acetyl CoA synthetase in these cells may be promising for anticancer treatment.